PB1922: THE FIRST REPORT OF REAL-WORLD OUTCOMES OF ZANUBRUTINIB MONOTHERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Jing Luo, Jiao-Jiao Zhang, Jin Wang, Jian‑qing MI
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: The second-generation Bruton’s Tyrosine Kinase inhibitor (BTKi) zanubrutinib had better BTK specificity and less off-target inhibition than first-generation BTKi ibrutinib. SEQUOIA study demonstrated superior efficacy of frontline zanubrutinib than bendamustine-rituximab combination, and ALPINE study demonstrated improved overall response rate (ORR) and progression free survival (PFS) of zanubrutinib than ibrutinib in relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Meanwhile, zanubrutinib had better safety profile than ibrutinib, especially relatively reduced cardiac toxicity. So far, the real-world efficacy and safety profile of zanubrutinib remain largely unknown. Aims: This is the first report to evaluate the effectiveness and safety of zanubrutinib monotherapy in Chinese CLL patients in a real-world setting. Methods: From Aug. 2020 to Sep. 2022, CLL pts received zanubrutinib monotherapy for at least 3 months were enrolled. Data cut-off time was Dec. 2022. Adverse events (AEs) were evaluated and graded according to CTCAE 5.0 and IWCLL criteria. Treatment interruption was defined as temporarily discontinuation of zanubrutinib. Treatment discontinuation was defined as permanently discontinuation of zanubrutinib without switching to any other BTKi. ORR included partial response with lymphocytosis or above. Results: In total, 72 pts were analyzed. 52 (72.2%) were treatment-naïve (TN) pts and 20 (27.8%) were R/R pts. Zanubrutinib was given 160mg, twice a day. The median age of zanubrutinib initiation was 68 years old (range, 37-87) with a M/F ratio of 2:1. Among evaluable pts, 42.3% had 13q deletion, 29.6% had 12 trisomy, 9.4% had 11q deletion, 26.2% had TP53 aberration (deletion and/or mutation) and 50.0% had unmutated IGHV. With a median follow-up time of 16.7 months, ORR of the entire cohort, TN and R/R pts were 93.1%, 96.2% and 85.0%, respectively. The median PFS and overall survival (OS) were not reached in the entire cohort. The estimated PFS and OS rates at 12 months were 91.3% (95%CI 87.9-94.7%) and 95.6% (95%CI 93.1-98.1%) (Fig.A-B). When stratified by line of therapy, the estimated 12-month PFS rates of TN and R/R pts were 92.2% (95%CI 88.4-96.0%) and 71.9% (95%CI 59.6-84.2%), and 12-month OS rates were 94.1% (95%CI 90.8-97.4%) and 77.1% (95%CI 65.4-88.8%), respectively. Pts over 65 years old had significantly inferior PFS (P=0.033), however, no significant impact of gender, Binet or Rai stages, front-line therapy, 11q deletion, TP53 aberration or IGHV mutation status on PFS or OS was observed. 55 (76.4%) pts experienced AEs of any grade, and 21 (29.2%) pts experienced AEs of grade 3 or above. The most common grade 3 or above AEs were neutropenia and pneumonia, and no atrial fibrillation/flutter was observed. AE was the most common reason of all types of treatment disruptions, accounting for 10 (13.9%) cases of dose reduction, 4 (5.6%) cases of zanubrutinib interruption and 7 (9.7%) cases of zanubrutinib discontinuation. Unfortunately, zanubrutinib discontinuation was associated with inferior PFS and OS (Fig. C-D).Summary/Conclusion: The real-world efficacy of zanubrutinib monotherapy in Chinese CLL pts was comparable to that of clinical trials. The toxicity spectrum was similar to data previously reported, and no atrial fibrillation/flutter was observed. Despite an improved safety profile, AE was the main reason of treatment discontinuation, and zanubrutinib discontinuation significantly associated with shorter PFS and OS. Therefore, early recognition and management of adverse events could help to prolong treatment exposure and ensure the efficacy of zanubrutinib. Keywords: Chronic lymphocytic leukemia, Real world data, Bruton’s tyrosine kinase inhibitor (BTKi)